Reducing Dendrimer Generation and PEG Chain Length Increases Drug Release and Promotes Anticancer Activity of PEGylated Polylysine Dendrimers Conjugated with Doxorubicin via a Cathepsin-Cleavable Peptide Linker

Dharmini Mehta, Nathania Leong, Victoria M. McLeod, Brian D. Kelly, Rashmi Pathak, David J. Owen, Christopher J.H. Porter, Lisa M. Kaminskas

Research output: Contribution to journalArticleResearchpeer-review

Abstract

PEGylation typically improves the systemic exposure and tumor biodistribution of polymeric drug delivery systems, but may also restrict enzyme access to peptide-based drug linkers. The impact of dendrimer generation (G4 vs G5) and PEG length (570 vs 1100 Da) on the pharmacokinetics, tumor biodistribution, drug release kinetics, and anticancer activity of a series of PEGylated polylysine dendrimers conjugated with doxorubicin via a cathepsin-B cleavable valine-citrulline linker was therefore investigated in rodents. Although the smallest G4 PEG570 dendrimer showed the most efficient cathepsin-mediated doxorubicin release, systemic exposure and tumor uptake were limited. The largest G5 PEG1100 dendrimer showed good tumor uptake and retention but restricted drug liberation and therefore limited anticancer activity. Superior anticancer activity was achieved using an intermediate sized dendrimer that showed better drug release kinetics, systemic exposure, tumor uptake, and retention. The data suggest that balancing PEG molecular weight and dendrimer size is critical when designing chemotherapeutic dendrimers.

Original languageEnglish
Pages (from-to)4568-4576
Number of pages9
JournalMolecular Pharmaceutics
Volume15
Issue number10
DOIs
Publication statusPublished - 1 Oct 2018

Keywords

  • biodistribution
  • cathepsin B
  • dendrimer
  • pharmacokinetics
  • tumor

Cite this

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title = "Reducing Dendrimer Generation and PEG Chain Length Increases Drug Release and Promotes Anticancer Activity of PEGylated Polylysine Dendrimers Conjugated with Doxorubicin via a Cathepsin-Cleavable Peptide Linker",
abstract = "PEGylation typically improves the systemic exposure and tumor biodistribution of polymeric drug delivery systems, but may also restrict enzyme access to peptide-based drug linkers. The impact of dendrimer generation (G4 vs G5) and PEG length (570 vs 1100 Da) on the pharmacokinetics, tumor biodistribution, drug release kinetics, and anticancer activity of a series of PEGylated polylysine dendrimers conjugated with doxorubicin via a cathepsin-B cleavable valine-citrulline linker was therefore investigated in rodents. Although the smallest G4 PEG570 dendrimer showed the most efficient cathepsin-mediated doxorubicin release, systemic exposure and tumor uptake were limited. The largest G5 PEG1100 dendrimer showed good tumor uptake and retention but restricted drug liberation and therefore limited anticancer activity. Superior anticancer activity was achieved using an intermediate sized dendrimer that showed better drug release kinetics, systemic exposure, tumor uptake, and retention. The data suggest that balancing PEG molecular weight and dendrimer size is critical when designing chemotherapeutic dendrimers.",
keywords = "biodistribution, cathepsin B, dendrimer, pharmacokinetics, tumor",
author = "Dharmini Mehta and Nathania Leong and McLeod, {Victoria M.} and Kelly, {Brian D.} and Rashmi Pathak and Owen, {David J.} and Porter, {Christopher J.H.} and Kaminskas, {Lisa M.}",
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Reducing Dendrimer Generation and PEG Chain Length Increases Drug Release and Promotes Anticancer Activity of PEGylated Polylysine Dendrimers Conjugated with Doxorubicin via a Cathepsin-Cleavable Peptide Linker. / Mehta, Dharmini; Leong, Nathania; McLeod, Victoria M.; Kelly, Brian D.; Pathak, Rashmi; Owen, David J.; Porter, Christopher J.H.; Kaminskas, Lisa M.

In: Molecular Pharmaceutics, Vol. 15, No. 10, 01.10.2018, p. 4568-4576.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Leong, Nathania

AU - McLeod, Victoria M.

AU - Kelly, Brian D.

AU - Pathak, Rashmi

AU - Owen, David J.

AU - Porter, Christopher J.H.

AU - Kaminskas, Lisa M.

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